Beruflich Dokumente
Kultur Dokumente
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ABSTRACT: Reaction of dimethylsulfonium methylide with Cinchona alkaloid ketones proceeds with complete
diastereoselectivity to give epoxides of 8,9-like conguration. The reaction of dimethylsulfoxonium methylide gives dierent
isomers, albeit with lower (4:1) selectivity. -Epimerization of the alkaloid ketones resulted in formation of two separable
diasteromeric products. The congurations of the epoxides were elucidated on the basis of NMR data combined with DFT
calculations. Models explaining observed selectivity are discussed. The epoxides were eciently transformed to a number of
derivatives through selective SN2-type ring-opening reactions with various nucleophiles, often without the need of additional
purication steps.
1. INTRODUCTION
Cinchona alkaloids, privileged transition metal ligands and
organocatalysts, enjoy continued interest for their numerous
applications in asymmetric synthesis.1 Nevertheless, there have
been relatively few successful modications to the alkaloid
carbon skeleton at the C-9 center. Few examples include the
introduction of additional CF3,2 simple alkyl, aryl and vinyl
groups,3 and the corresponding ring rearrangements.4 An
attractive approach to the extension of carbon framework is
oered by the CoreyChaykovsky reaction of sulfur ylides5
with the respective 9-carbonyl compounds. Generally, the
stereochemistry of epoxides resulting from the Corey
Chaykovsky reaction can be controlled by the use of stabilized
chiral sulfur ylides6 or chiral lithiumlanthanide complexes.7
Highly diastereoselective reaction was also noted for the
adequately substituted cyclic ketones.8 However, in the case of
acyclic ketones with a stereogenic center at the -position,
rather fair diastereoselectivities have been found.9
The feasibility of epoxides for further transformations makes
them valuable synthetic intermediates. As a result, a library of
multifunctional derivatives of Cinchona alkaloids relevant to
organocatalysis1,10 and metalorganic frameworks11 can be
envisaged.
Similar results were also obtained for other solvent and base
combinations13 (like potassium tert-butoxide in THF). After an
aqueous workup, the epoxides were obtained as a mixture of
two diastereomers in very high (8090%) yield. No other
isomeric products could be detected by NMR. However, when
instead of trimethylsulfonium, respective sulfoxonium iodide
was used, all of the four possible isomers were identied in the
crude mixture (Scheme 2). This is in contrast to the usually
observed higher selectivity of the sulfoxonium reagents.14
The epoxides from the reaction of trimethylsulfonium iodide
were formed with essentially invariable diastereomeric ratio of
7:6, regardless of the base, solvent, and addition sequence.
Chromatography of the initial mixtures on silica gel did not
separate the isomers; however, fractional crystallization allowed
for isolation of pure diastereomers. Crystallization from tertbutyl methyl ether was particularly ecient for cinchoninederived epoxides CN-2 and CD-2 (Scheme 1). In the rst crop
pure CN-2 was isolated in 30% yield. Pure CD-2 was obtained
by sequential crystallization or a chromatography of the
enriched mother liquor followed by recrystallization from
diethyl ether. Unfortunately this separation procedure did not
translate well to the quinidine-series epoxides. There, only QD2 could be isolated in high diastereomeric purity by
crystallization from diethyl ether. However, each of the two
additional isomers (QD-3 and QN-3) formed in the reaction of
trimethylsulfoxonium iodide (Scheme 2) was separated by
chromatography.
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Figure 2. DFT/B3LYP/6-31G(d,p) optimized structures and selected NOESY interactions (dashed lines) for CN-2 (left) and CD-2 (right). Strong
interactions are marked in red, weak in magenta (for details, see Section S3.3, Supporting Information).
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Figure 3. DFT/B3LYP/6-31G(d,p) low energy conformations and reactivity of CN-1. Re and Si faces of carbonyl group are marked.
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3. CONCLUSIONS
The diastereoselective CoreyChaykovsky reaction of the
Cinchona alkaloid ketones led to the corresponding 9epoxymethyl derivatives in good yields. The reaction with
dimethylsulfonium methylide occurred at the face opposite to
the nitrogen lone pair, resulting exclusively in the 8,9-like
conguration. Particularly, (9R)-9-epoxymethyl-cinchonine
(CN-2) was easily prepared from the commercially available
alkaloids, without the use of chromatography. The reaction of
dimethylsulfoxonium methylide gave predominantly the
epoxides of 8,9-unlike conguration. The selective SN2 ringopening of epoxides with various oxygen, sulfur, and nitrogen
nucleophiles gave multifunctional aminoalcohols, chiral building blocks for prospective catalysts.
respective azide CN-8. In this case the crude product did not
require further purication, and the yield was nearly
quantitative (Scheme 5).
The azide CN-8 reacted with phenylacetylene in the
copper(I)-catalyzed 1,3-dipolar cycloaddition click reaction
giving the corresponding triazole CN-9. Also, the azide CN-8
was reduced to the corresponding amine CN-10 with LiAlH4.23
Although the isolation of pure aminoalcohol CN-10 was
ineective, the crude product was used for further transformations. Alternatively, the azide CN-8 was rst converted to
the corresponding silyl ether CN-11, which was reduced under
the Staudinger conditions to the more tangible aminoether CN12. The reaction of crude CN-10 with 3,5-bis(triuoromethyl)phenyl isothiocyanate gave the corresponding thiourea CN-13.
Apart from the desired thiourea, also oxazolidinethione CN-14
was isolated from the reaction mixture. Oxazolidinethione CN14 was independently obtained in the reaction of CN-10 and
carbon disulde. It was also found to form in the heated sample
of CN-13 in DMSO. However, under similar conditions
thiourea with silyl ether group CN-15 was stable. Amine CN10 was also converted to the amide CN-16 with acetic
anhydride.
The epoxide CN-2 reacted with benzylamine in the presence
of lithium perchlorate at 100 C, giving the corresponding
secondary amine CN-17. Treatment of the aminoalcohol CN17 with an excess of acetic anhydride gave the N-acetylated
product CN-18 with unmodied 9-hydroxyl group.
Hydrogenation of CN-2 on 10% Pd/C occurred solely at the
vinyl group of the alkaloid. The product DHCN-2 was identical
to one of the isomers obtained in the epoxidation of 10,11dihydrocinchoninone (DHCN-1, Scheme 6). The epoxides
could not be eciently opened by Grignard reagents or by
LiAlH4.
4. EXPERIMENTAL SECTION
NMR spectra were internally referenced to solvent signals: 1H 7.26 for
CHCl3, 2.50 for DMSO-d5, and 13C 77.16 for CDCl3, 39.52 for
DMSO-d6. High resolution mass spectra (TOF) were obtained in
electrospray ionization mode. All reagents were purchased from
commercial suppliers and used as received, CN-1, and QD-1 were
prepared according to literature procedures.3,13 DHCN-1 was
prepared following the literature procedure used for CN-13b from
10,11-dihydrocinchonidine and recrystallized from Et2O in 62% yield.
10,11-Dihydrocinchonanone (DHCN-1). Yellow crystalline
solid: mp 121124 C (Et2O), 122125 C (EtOH) (lit.15 mp 138
C (EtOH)); 1H NMR (CDCl3, 300 MHz) 8.97 (d, J = 4.4 Hz, 1H),
8.20 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.72 (ddd, J = 8.5,
6.9, 1.4 Hz, 1H), 7.64 (d, J = 4.4 Hz, 1H), 7.58 (ddd, J = 8.4, 6.9, 1.3
Hz, 1H), 4.16 (m, 1H), 3.12 (dd, J = 13.6, 9.2 Hz, 1H), 2.77 (m, 1H),
2.502.74 (m, 2H), 2.07 (m, 1H), 1.83 (m, 1H), 1.77 (m, 1H), 1.63
(m, 1H), 1.331.51 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR
(CDCl3, 75.5 MHz) 203.2, 149.8, 149.2, 143.4, 130.2, 129.7, 128.0,
125.1, 124.6, 119.5, 63.4, 57.4, 43.5, 37.4, 28.0, 27.6, 25.2, 21.6, 12.2.
CoreyChaykovsky Reaction of CN-1 and Dimethylsulfonium Methylide. In a 100 mL round-bottom ask were placed
recrystallized cinchoninone3 (11.9g, 40.8 mmol), trimethylsulfonium
iodide (8.67 g, 42.4 mmol, 1.04 equiv), and DMSO (64 g). The
suspension was stirred for 5 min, and potassium hydroxide (akes
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90%, 2.65 g, 41.8 mmol, 1.03 equiv) was added. Within a few minutes
the mixture turned deep red and became temporarily homogeneous.
After a few hours a precipitate formed and the mixture turned light
orange. The mixture was stirred for a total of 52 h, and then it was
diluted with diethyl ether (450 mL),24 washed with brine (8 50 mL),
and dried over Na2SO4. On evaporation, a mixture of CN-2 and CD-2
(11.1 g, 90%) was obtained. Repeated procedures on 0.132 g scale
gave 8090% yields.
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2.552.82 (m, 3H), 2.102.25 (m, 2H), 1.341.64 (m, 3H); 13C
NMR (CDCl3, 75.5 MHz) 151.8 (br.), 149.4, 148.2, 140.9, 130.0,
128.6, 126.4, 125.8, 125.4, 120.3, 114.5, 80.4, 66.2, 61.8, 50.4, 49.7,
40.2, 29.0, 26.6, 22.4; IR (KBr) 3452, 3254, 3101, 2916, 2865, 1579,
1513, 1454, 1110, 1070, 1050, 909, 826, 770 cm1; HRMS calcd. for
[C20H24N2O2 + H]+ 325.1911, found 325.1905.
9S-Hydroxymethyl-cinchonidine (CD-4). Compound was obtained analogously to CN-4. Starting from 625 mg (2.04 mmol) of
CD-2, 189 mg (28%) of CD-4 was obtained as white solid: mp 150
156 C; 1H NMR (CDCl3, 300 MHz, 313 K) 8.34 (m, 1H), 8.26 (d,
J = 8.2 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 4.7 Hz, 1H),
7.347.48 (m, 2H), 5.89 (ddd, J = 17.4, 9.8, 7.3 Hz, 1H), 4.965.05
(m, 2H), 4.35 (br., 2H), 4.32 (d, J = 11.1 Hz, 1H), 3.81 (d, J = 11.1
Hz, 1H), 3.53 (t, J = 8.9 Hz, 1H), 3.16 (m, 1H), 2.84 (dd, J = 13.6,
10.4 Hz, 1H), 2.52 (m, 1H), 2.30 (m, 1H), 2.20 (m, 1H), 2.03 (m,
1H), 1.86 (m, 1H), 1.661.84 (m, 2H), 1.38 (m, 1H); 13C NMR
(CDCl3, 75.5 MHz, 313 K) 152.0, 149.4, 148.4, 142.4, 130.2, 128.5,
126.7, 125.8, 125.3, 120.3 114.2, 80.5, 66.5, 62.0, 57.6, 43.4, 40.0, 28.6,
27.7, 22.9; IR (KBr) 3465, 3102, 2934, 2872, 1583, 1512, 1386, 1070,
921, 820, 767 cm1; HRMS calcd. for [C20H24N2O2 + H]+ 325.1911,
found 325.1907.
9R-Phenylsulfanylmethyl-cinchonine (CN-5). Epoxide CN-2
(110 mg, 0.36 mmol) and thiophenol (0.10 mL, 0.96 mmol, 2.7 equiv)
were dissolved in ethanol (96%, 5 mL), and sodium hydroxide (12.5
mg, 0.31 mmol, 0.86 equiv) was added. The mixture was stirred for 18
h at room temperature and diluted with diethyl ether (35 mL), washed
with 10% aqueous NaOH (2 20 mL), and extracted with 2 M HCl
(30 mL). Acidic extracts were treated with excess Na2CO3 and
extracted with CH2Cl2, dried over Na2SO4 and evaporated to give 136
mg (90%) of CN-5 as amorphous solid: 1H NMR (CDCl3, 300 MHz,
318 K) 8.76 (d, J = 4.7 Hz, 1H), 8.38 (br, 1H), 8.06 (dd, J = 8.4, 1.3
Hz, 1H), 7.72 (br. 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.63 (br. 1H), 7.57
(ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.42 (ddd, J = 8.7, 6.9, 1.5 Hz, 1H),
7.017.06 (m, 2H), 6.947.00 (m, 3H), 5.99 (ddd, J = 17.2, 10.6, 7.3
Hz, 1H), 5.01 (ddd, J = 10.6, 1.6, 1.3 Hz), 4.98 (ddd, J = 17.2, 1.6, 1.4
Hz, 1H), 4.1 (br., 1H), 4.09 (d, J = 13.4 Hz, 1H), 3.55 (t, J = 9.4 Hz,
1H), 3.48 (d, J = 13.4 Hz, 1H), 3.04 (ddd, J = 13.9, 7.9, 2.2 Hz, 1H),
2.462.71 (m, 3H), 2.27 (t, J = 10.8 Hz, 1H), 2.11 (q, J = 8.3 Hz, 1H),
1.82 (m, 1H), 1.411.63 (m, 3H); 13C NMR (CDCl3, 75.5 MHz, 318
K) 150.6, 149.5, 149.3, 140.8, 134.9, 131.1, 130.7, 128.6, 128.0,
126.8, 125.62, 125.58, 125.3, 120.2, 114.2, 79.9, 63.4, 50.8, 49.7, 45.8,
40.1, 29.2, 26.7, 22.3; IR (KBr) 3434, 3071, 2933, 2869, 1582, 1510,
1439, 1301, 1103, 1089, 759, 741, 690 cm1; HRMS (ESI) calcd. for
[C26H28N2OS + H]+ 417.1995, found 417.1985.
9R-(2-Aminophenyl)-sulfanylmethyl-cinchonine (CN-6). Lithium hydride (26 mg, 2.6 mmol, 2.3 equiv) was suspended in a solution
of 2-aminothiophenol (0.26 mL, 2.43 mmol, 2.2 equiv) in DMF (1
mL), and stirred until a clear solution was obtained (ca. 15 min). Then
epoxide CN-2 (356 mg, 1.11 mmol) was added, the suspension was
stirred for 5 min, and additional DMF (1 mL) was added. The mixture
was stirred for 18 h at room temperature, evaporated in vacuo (50 C),
and dried in a vacuum desiccator over H2SO4. The residue was
dissolved in ethyl acetate (50 mL) and washed with brine (3 10
mL), dried over Na2SO4 and evaporated. Chromatography on silica gel
(CHCl3/MeOH 10:1) gave 442 mg (93%) of CN-6 as a yellowish
amorphous solid: 1H NMR (CDCl3, 300 MHz, 313 K) 8.79 (d, J =
4.8 Hz, 1H), 8.39 (br., 1H), 8.08 (dd, J = 8.5, 1.3 Hz, 1H), 7.65 (br.
1H), 7.58 (ddd, J = 8.5, 7.0, 1.1 Hz, 1H), 7.41 (ddd, J = 8.4, 7.0, 1.3
Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.44 (d, J =
7.7 Hz, 1H), 6.41 (t, J = 7.5 Hz, 1H), 5.94 (m, 1H), 4.98 (dt, J = 10.2,
1.3 Hz, 1H), 4.95 (dd, J = 17.3, 1.2 Hz, 1H), 4.1 (br., 2H), 4.04 (d, J
= 13.1 Hz, 1H), 3.44 (t, J = 8.3 Hz, 1H), 3.24 (d, J = 13.1 Hz, 1H),
3.00 (m, 1H), 2.452.70 (m, 3H), 2.042.24 (m, 2H), 1.78 (m, 1H),
1.371.58 (m, 3H); 13C NMR (CDCl3, 75.5 MHz, 318 K) 149.7,
149.4, 148.0, 142.4, 140.8, 135.7, 131.1, 130.0, 128.2, 127.0, 125.7 (2C
overlap), 120.4, 119.0, 117.8, 115.2, 114.4, 80.6, 63.9, 51.0, 49.9, 46.1,
40.2, 29.3, 26.7, 22.5; IR (KBr) 3434, 3302, 3175, 3066, 2934, 2870,
1609, 1581, 1479, 1449, 1303, 910, 752 cm1; HRMS (ESI) calcd. for
[C26H29N3OS + H]+ 432.2104, found 432.2097.
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1H), 1.62 (m, 1H), 1.381.51 (m, 2H); 1H NMR (CDCl3, 600 MHz,
273K, mixture of conformers 1:1) 9.06 (d, J = 8.8 Hz, 1H), 8.68 (d,
J = 4.7 Hz, 1H), 8.67 (d, J = 4.7 Hz, 1H), 8.58 (br. m, 1H), 8.25 (d, J =
8.6 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 8.06 (br., 1H), 8.04 (d, J = 8.3
Hz, 1), 7.72 (t, J = 7.4 Hz, 1H), 7.70 (d, J = 4.7 Hz, 1H), 7.627.68
(m, 4H), 7.50 (t, J = 7.7 Hz, 1H), 7.45 (d, J = 7.5 Hz, 2H), 7.35 (d, J =
4.7 Hz, 1H), 7.267.32 (m, 4H), 7.217.24 (m, 1H), 6.07 (ddd, J =
17.6, 10.0, 7.6 Hz, 1H), 6.0 (br, 1H), 5.85 (ddd, J = 17.3, 10.5, 6.6
Hz, 1H),), 5.10 (d, J = 10.5 Hz, 1H), 5.005.07 (m, 3H), 4.98 (d, J =
14.2 Hz, 1H), 3.77 (t, J = 9.0 Hz, 1H), 3.34 (t, J = 9.9 Hz, 1H), 2.99
3.09 (m, 3H), 2.87 (m, 1H), 2.642.74 (m, 2H), 2.522.62 (m, 2H),
2.452.50 (m, 1H), 2.27 (q, J = 8.0 Hz, 1H), 2.15 (q, J = 8.1 Hz, 1H),
1.781.90 (m, 3H), 1.471.66 (m, 5H), 1.30 (m, 1H); 13C NMR
(DMSO-d6, 75.5 MHz, 333 K) 149.1, 148.9, 148.2, 145.2, 140.7,
130.4, 129.8, 128.3, 127.5, 127.2, 126 (br.), 125.9, 125.1, 124.7,
121.9, 119.7, 113.5, 80.3, 60.5, 57.0, 49.3, 48.4, 39.2, 28.2, 25.7, 20.7;
IR (KBr) 3408, 2934, 2871, 1581, 1510, 1456, 1232, 1201, 1047, 764,
695 cm1; HRMS calcd. for [C28H29N5O + H]+ 452.2445, found
452.2434.
9S-Aminomethyl-cinchonine (CN-10). Azide CN-8 (1.42 g, 4.07
mmol) was dissolved in THF (15 mL) and cooled to 0 C. LiAlH4
(159 mg, 4.18 mmol, 1.03 equiv) was added, the mixture was stirred
for 15 min at 0 C followed by another portion of LiAlH4 (15.4 mg,
0.40 mmol, 0.10 equiv), and the mixture was stirred for additional 10
min. The reaction was quenched by addition of brine, extracted with
CH2Cl2, dried over Na2SO4, and evaporated. The crude mixture was
used without further purication. A sample was puried on silica gel
with CHCl3/MeOH (5:1) followed by MeOH: 1H NMR (CDCl3, 300
MHz, 313 K) 8.85 (d, J = 4.6 Hz, 1H), 8.39 (br., 1H), 8.14 (d, J =
8.3 Hz, 1H), 7.78 (br., 1H), 7.64 (m, 1H), 7.48 (m, 1H), 6.06 (m,
1H), 4.975.05 (m, 2H), 3.61 (d, J = 12.4 Hz, 1H), 3.55 (m, 1H),
3.13 (m, 1H), 3.00 (d, J = 12.4 Hz, 1H), 1.972.90 (m, 7H), 1.82 (m,
1H), 1.401.67 (m, 3H); HRMS (ESI) calcd. for [C20H25N3O + H]+
324.2072, found 324.2082.
O-tert-Butyldimethylsilyl-9S-azidomethyl-cinchonine (CN11). Azide CN-8 (544 mg, 1.56 mmol) was dissolved in dichloromethane (9 mL), and triethylamine (0.25 mL, 1.79 mmol, 1.15 equiv)
was added. The mixture was cooled to 0 C, a rst portion of TBDMS
triate (0.50 mL) was added, and then the mixture was allowed to
attain room temperature, and after 2.5 h another portion of TBDMS
was added (0.25 mL; total 3.27 mmol, 2.1 equiv). The mixture was
stirred at room temperature for 18 h, and ltered through a pad of
silica gel with CHCl3/MeOH 10:1. After evaporation, the residue
(1.40 g) was triturated with 10% aqueous NaOH, extracted with
CH2Cl2, dried over Na2SO4, evaporated, and washed with 0.3 mL of
hexane to give 656 mg (90%) of product as o-white crystalline solid:
1
H NMR (CDCl3, 300 MHz) 8.87 (d, J = 4.8 Hz, 1H), 8.72 (d, J =
8.8 Hz, 1H), 8.12 (dd, J = 8.4, 1.1 Hz, 1H), 7.66 (ddd, J = 8.1, 6.8, 1.1
Hz, 1H), 7.58 (br., 1H), 7.50 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 5.31
(ddd, J = 17.0, 10.4, 6.2 Hz, 1H), 4.72 (d, J = 13.4 Hz, 1H), 4.68 (d, J
= 10.5 Hz, 1H), 4.44 (d, J = 17.1 Hz, 1H), 4.06 (d, J = 13.4 Hz, 1H),
3.21 (t, J = 9.5 Hz, 1H), 2.96 (m, 1H), 2.68 (dt, J = 13.1, 8.8 Hz, 1H),
2.42 (m, 1H), 1.882.00 (m, 2H), 1.521.76 (m, 3H), 1.391.52 (m,
2H), 0.99 (s, 9H), 0.28 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3, 75.5
MHz) 149.3, 149.2, 147.6, 139.4, 130.6, 128.7, 127.6, 127.4, 125.9,
122.1, 114.4, 84.0, 64.5, 58.9, 51.5, 49.6, 39.5, 28.9, 26.5, 26.0, 22.5,
19.4, 1.8, 2.2; IR (KBr) 3065, 2955, 2860, 2108, 1512, 1472, 1259,
1160, 1030, 838, 779, 638 cm 1 ; HRMS (ESI) calcd. for
[C26H37N5OSi + H]+ 464.2840, found 464.2837.
O-tert-Butyldimethylsilyl-9S-aminomethyl-cinchonine (CN12). Azide CN-11 (80.6 mg, 0.173 mmol) was dissolved in THF (4
mL), and triphenylphosphine (69.9 mg, 0.267 mmmol, 1.54 equiv)
was added. The mixture was stirred at 45 C for 18 h and then allowed
to attain room temperature. Water (0.5 mL) was added, and the
mixture was stirred for additional 24 h, and extracted with CHCl3,
dried over Na2SO4, and evaporated. Chromatography on silica gel
(CHCl3/MeOH 10:1) gave 46 mg (61%) of CN-12 as colorless oil: Rf
0.38 (CHCl3/MeOH, 10:1); 1H NMR (CDCl3, 300 MHz) 8.86 (d, J
= 4.6 Hz, 1H), 8.79 (d, J = 8.7 Hz, 1H), 8.10 (dd, J = 8.3, 1.2 Hz, 1H),
7.64 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.58 (br., 1H), 7.48 (ddd, J = 8.7,
6.8, 1.5 Hz, 1H), 5.44 (ddd, J = 17.2, 10.5, 7.1 Hz, 1H), 4.75 (d, J =
10.5 Hz, 1H), 4.55 (d, J = 17.2 Hz, 1H), 4.04 (br. m, 1H), 3.153.29
(m, 2H), 2.94 (m, 1H), 2.66 (ddd, J = 13.2, 8.8, 8.6 Hz, 1H), 2.48 (m,
1H), 2.13 (m, 1H), 1.96 (q, J = 7.9 Hz, 1H), 1.64 (m, 1H), 1.111.62
(m, 6H), 0.95 (s, 9H), 0.32 (s, 3H), 0.17 (s, 3H); 13C NMR (CDCl3,
75.5 MHz) 149.5, 149.4, 149.3, 139.8, 132.1, 130.6, 128.6, 127.2,
126.0, 122.2, 114.2, 87.1, 64.3, 51.5, 49.9, 49.2, 39.5, 28.9, 26.7, 26.0,
22.9, 19.6, 1.9, 2.1; IR (neat) 3394, 3299, 2930, 2857, 2576, 1508,
1472, 1249, 1120, 1093, 1055, 982, 834, 776 cm1; HRMS (ESI) calcd.
for [C26H39N3OSi + H]+ 438.2935, found 438.2949.
N-3,5-Bis(triuoromethyl)phenyl-N-(8R,9S-9-hydroxy-cinchonan-9-yl-methyl)-thiourea (CN-13). Crude mixture containing
CN-10 (1.12 g) was dissolved in DCM (20 mL), and 3,5bis(triuoromethyl)phenyl isothiocyanate (934 mg, 3.44 mmol) was
added. The mixture was stirred for 18 h, concentrated to about 10 mL,
and subjected to chromatography on silica gel (CHCl3/MeOH 10:1 to
5:1). Obtained was 800 mg (41% over 2 steps) of CN-13. Additionally
30 mg (3%) of CN-14 was isolated. CN-13: mp 120128 C; 1H
NMR (CDCl3, 300 MHz, 313 K) 9.5 (br., 1H), 8.5 (br. 1H),
8.25 (br. 1H), 7.87 (s, 2H), 7.527.76 (br. m, 3H), 7.55 (s, 1H),
7.407.49 (m, 2H), 6.00 (ddd, J = 17.1, 10.5, 7.0 Hz 1H), 5.10 (d, J =
10.5 Hz, 1H), 5.07 (d, J = 17.1 Hz, 1H), 4.74 (br. 1H), 4.39 (br. d, J =
13 Hz, 1H), 3.48 (br., 1H), 3.03 (dd, J = 13.0, 7.9 Hz, 1H), 2.55
3.81 (br. m, 3H), 2.152.29 (m, 2H), 1.89 (m, 1H), 1.471.66 (m,
3H); 13C NMR (CDCl3, 75.5 MHz, 313 K) 183.6, 151 (br.), 149.0,
148.3 (br.), 140.4, 139.6, 132.2 (q JCF = 34 Hz), 129.3, 129.2, 126.7,
126 (br.), 123.7, 123.1 (q JCF = 273 Hz), 118.6 (sept J = 4 Hz),
115.1, 81.5, 62.8, 51.7, 50.9, 49.8, 39.7, 28.9, 26.3, 22.4 (2 sp2 C
missing due to coalescence and overlaps); IR (KBr) 3366, 2940, 1576,
1513, 1471, 1381, 1279, 1177, 1133, 759 cm1; HRMS (ESI) calcd. for
[C29H28F6N4OS + H]+ 595.1961, found 595.1946.
5S-5-(Quinolin-4-yl)-5-((1S,2R,5R)-5-vinyl-quinuclidin-2-yl)oxazolidine-2-thione (CN-14). Crude mixture containing CN-10
(28 mg) was dissolved in THF (1.5 mL). Triethylamine (0.11 mL,
0.79 mmol) and carbon disulde (0.06 mL, 0.99 mmol) were added,
and the mixture was stirred at 5060 C for 20 h. The mixture was
briey evaporated and puried on silica gel (CHCl3/MeOH, 10:1)
giving 18.6 mg (58% over 2 steps) of white crystalline solid After
chromatography the sample became insoluble in CHCl3: mp 273275
C (dec); 1H NMR (DMSO-d6/H2O, 600 MHz) 10.26 (br, 1H),
8.88 (d, J = 4.6 Hz, 1H), 8.08 (dd, J = 8.4, 0.9 Hz, 1H), 7.96 (br. d, J =
8.4 Hz, 1H), 7.77 (ddd, J = 6.7, 8.1, 0.9 Hz, 1H), 7.597.62 (m,
2H), 6.19 (ddd, J = 17.0, 10.4, 8.2 Hz, 1H), 5.06 (dd, J = 17.0, 1.9 Hz,
1H), 4.99 (dd, J = 10.4, 1.9 Hz, 1H), 4.35 (d, J =10.8 Hz, 1H), 3.93 (d,
J =10.8 Hz, 1H), 3.83 (t, J = 8.2 Hz, 1H), 2.89 (dd, J = 12.9, 7.4 Hz,
1H), 2.45 (t, J = 12.0 Hz, 1H), 2.232.31 (m, 2H), 2.09 (q, J = 8.6 Hz,
1H), 1.83 (m, 1H), 1.721.78 (m, 2H), 1.56 (q, J = 10.6 Hz, 1H),
1.41 (m, 1H); 13C NMR (DMSO-d6/H2O, 151 MHz) 186.1, 150.0,
148.8, 148.4, 141.0, 130.5, 129.0, 126.7, 123.5, 124.2, 117.2, 115.0,
93.9, 62.0, 53.2, 49.6, 48.4, 40.1, 28.7, 25.8, 20.4; IR (KBr) 2942, 2872,
1547, 1511, 1317, 1277, 1173, 1132, 912, 776, 759 cm1; HRMS (ESI)
calcd. for [C21H23N3OS + H]+ 366.1636, found 366.1651.
N-((8R,9S)-9-(tert-Butyldimethylsilyloxy)-cinchonan-9-ylmethyl)-N-3,5-bis(triuoromethyl)phenyl-thiourea (CN-15).
Amine CN-12 (44.0 mg, 0.10 mmol) was dissolved in CH2Cl2 (4
mL), and 3,5-bis(triuoromethyl)phenyl isothiocyanate (19 L, 0.10
mmol, 1.0 equiv) was added. The mixture was stirred for 28 h and
then chromatographed on silica gel (CHCl3/MeOH 20:1) to give 56.5
mg (80%) of product as solidifying oil: 1H NMR (CDCl3, 300 MHz,
318 K) 8.79 (d, J = 8.8 Hz, 1H), 8.72 (br., 1H), 8.62 (br., 1H),
7.90 (br., 1H), 7.70 (s, 2H), 7.69 (m, 1H), 7.5 (br. 1H), 7.57 (s,
1H), 7.50 (m, 1H), 7.47 (br. 1H), 5.36 (m, 1H), 4.724.83 (m, 2H),
4.59 (d, J = 17.2 Hz, 1H), 4.33 (d, J = 14.4 Hz, 1H), 3.45 (t, J = 9.6
Hz, 1H), 2.94 (t, J = 11.0 Hz, 1H), 2.312.59 (m, 2H), 1.892.07 (m,
2H), 1.63 (m, 1H), 1.381.59 (m, 3H), 1.06 (m, 1H), 0.86 (s, 9H),
0.34 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3, 75.5 MHz, 318 K)
181.6, 149.1, 148.1 (br.), 140.0, 139.2, 132.9 (q, J = 32 Hz), 129.7,
128.7 (br.), 127.7, 127.2, 126.4, 123.3, 123.0 (q, J = 273 Hz), 121.0
(br.), 118.7, 114.6 (br.), 83.1 (br.), 65.3, 55.0 (br.), 51.5, 49.6, 39.1,
29.0, 26.5, 25.9, 23.4, 19.3, 1.9, 2.5 (1 sp2 C missing due to
H
Article
ASSOCIATED CONTENT
S Supporting Information
*
Supporting tables and gures. Additional spectral and computational details including tables of atom coordinates and absolute
energies. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: przemyslaw.boratynski@pwr.wroc.pl.
Notes
ACKNOWLEDGMENTS
The work was nanced by a statutory activity subsidy from the
Polish Ministry of Science and Higher Education for the
Faculty of Chemistry of Wrocaw University of Technology.
We thank Wrocaw Networking and Supercomputing Center
for allotment of computer time and Mr. ukasz Toma for
synthesis of DHCN-1.
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